Surgery increases the risk of thrombosis but prevention and management of thromboembolic disease in the perioperative period is complicated by the risk of hemorrhage. Neutrophils (PMNs) play a vital role in wound healing, but their contribution to perioperative thrombosis and implications for thromboprophylaxis are now emerging. Adherence of PMNs to wounds and to the vasculature generates a unique localized sequestrum enriched in enzymes and antimicrobial peptides protected from plasma inhibitors that contribute to innate immunity in part through the orderly formation and dissolution of fibrin. We posit that post-operative and persistent inflammation disrupt this balance, predisposing to thrombosis by promoting formation and persistence of fibrin. We have previously observed that a-defensins (a-def), antimicrobial peptides that constitute 5% of total human PMN protein that are released upon activation, promote clotting and inhibit fibrinolysis. The absence of a-def in murine PMNs has hindered a better understanding of how these peptides contribute to thromboembolic disease in the perioperative setting. Using a novel transgenic mouse that expresses PMN a-def (Def++), we show that a-def circulates in a complex with fibrinogen and promotes polymerization and retraction of fibrin in vitro, deposits in the vasculature, induces occlusive arterial and venous thrombosis, and inhibits lysis of pulmonary emboli in vivo. These pathogenic properties can be transferred to wild type animals by transplanting bone marrow from Def++ mice and can be prevented and reversed by immunodepleting PMNs or by inhibiting a-def release using colchicine. We now propose an integrated approach to understanding the mechanism and implications of PMN a-def on perioperative thrombosis by examining: a) The biophysical effects of a-def on clot formation and structure; b) The mechanism of accelerated thrombosis and impaired fibrinolysis in Def++ mice and the salutary effect of blocking a-def release; and c) The utility of a-def expression as a biomarker for risk of venous thromboembolism post- surgery. These studies will provide insight into an unappreciated contribution of PMN a-def to arterial and venous thrombosis, identify novel genetic and protein biomarkers of patients at risk for surgery related thrombosis and provide evidence for the use of a safe and effective intervention to prevent thrombosis in the perioperative period.